A1 adenosine receptor agonists and methods of use thereof

ABSTRACT

Disclosed are compounds of the formulas (I), (II), and (II): which are A1 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and a method of use of these compounds, wherein Y, R1-R6, R10-R15, and R20-R22 are as defined in the specification. These compounds are selective to the A1 adenosine receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, for inducing and/or maintaining a hypothermic and/or hypometabolic state for treatment of a mammal.

CROSS REFERENCE TO A RELATED APPLICATION

This patent application claims the benefit of U.S. Provisional PatentApplication No. 62/776,528, filed Dec. 7, 2018, the disclosure of whichis incorporated herein by reference in its entirety for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant Numbers ZIADK031117-28, ZIA DK075063, and NIA AG000356 awarded by the NationalInstitutes of Health. The Government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

The A₁ adenosine receptor (A₁AR) is coupled to the inhibition ofadenylyl cyclase through the Gi protein and also acts on ion channelsand MAP kinases (1, 2). A₁AR agonists are desired for theirantiarrhythmic, antilipolytic, antinociceptive, cerebroprotective,cardioprotective, antidepressant, sleep-enhancing and antiseizureproperties (1-7). Beneficial peripheral effects of A₁AR agonists includeprotection in acute and chronic pain (8, 9) or as antilipolytic agents(10). The induction of mouse hypothermia through brain A₁AR activationthat is independent of peripheral A₃AR activation was recently described(14). Pharmacologically-induced hypothermia has potential clinicalapplications, such as cerebroprotection in brain ischemia, but most A₁ARagonists are unsuitable as clinical candidates because of theircardiovascular effects (1, 4, 11-13). Thus, there is a need for novelA₁AR agonists that are well-tolerated for a variety of clinicalapplications, but with diminished side effects.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula (I):

wherein Y is N or CH,

R¹ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl ordicyclodecylmethyl,

R² and R⁶ are independently selected from hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy,and C₁-C₆ alkylamino;

R³ and R⁴ are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; and

R⁵ is selected from hydrogen, hydroxyl, halo, C₁-C₃ alkyl aminocarbonyl,hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃ alkyl) aminocarbonyl, C₁-C₃alkylthio C₁-C₃ alkyl, halo C₁-C₃ alkyl, hydrazinyl, amino C₁-C₃ alkyl,hydroxy C₁-C₃ alkyl, C₃-C₆ cycloalkylamino, hydroxylamino, and C₂-C₃alkenyl;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (II):

wherein Y is N or CH,

R¹⁰ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl,dicyclodecylmethyl, or endo-2-norbornyl,

R¹¹ and R¹⁵ are independently selected from hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy,and C₁-C₆ alkylamino;

R¹² and R¹³ are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; and

R¹⁴ is selected from hydrogen, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylaminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃ alkyl)aminocarbonyl, C₃-C₈ cycloalkyl aminocarbonyl, C₁-C₃ alkylthio C₁-C₃alkyl, C₆-C₁₀ arylthio C₁-C₃ alkyl, halo C₁-C₃ alkyl, hydrazinyl, aminoC₁-C₃ alkyl, hydroxy C₁-C₃ alkyl, C₃-C₆ cycloalkylamino, hydroxylamino,and C₂-C₃ alkenyl, wherein the aryl portion of arylthio is optionallysubstituted with one or more substituents selected from halo and C₁-C₃alkoxy;

or a pharmaceutically acceptable salt thereof.

The invention further provides a compound of formula (III):

wherein R²⁰ is amino, C₁-C₃ alkoxy, C₁-C₃ alkylamino, hydroxy C₁-C₃alkylamino, di(C₁-C₃ alkyl)amino, or C₃-C₈ cycloalkylamino, and

R²¹ and R²² are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl,

or a pharmaceutically acceptable salt thereof.

The invention also provides a method of inducing and/or maintaining ahypothermic and/or hypometabolic state for treatment of a mammal,comprising administering to the mammal an effective amount of a compoundor salt of any one of the compounds of the invention.

The invention further provides a method of inducing and/or maintaining ahypothermic and/or hypometabolic state in a mammal, comprisingadministering to the mammal an effective amount of a compound or salt ofany one of the compounds of the invention, wherein the mammal issubjected to a surgical procedure.

The invention additionally provides a method of treating a disease ordisorder in a mammal in need thereof, wherein the disease or disorder isselected from chronic pain, acute pain, diabetes, cardiac arrhythmia,myocardial infarction, depression, and brain ischemia, comprisingadministering to the mammal an effective amount of a compound or salt ofany one of the compounds of the invention.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1A shows graphically functional activity of agonists 2 and 7, instimulation of guanine nucleotide binding at the rA₁AR from recombinantA₁AR membrane preparations from CHO-K1 cells, Perkin Elmer, as comparedto 2.

FIG. 1B shows graphically the effects of agonists 7 and 16 in inhibitionof cAMP accumulation at hA₃AR (in A₃AR-expressing CHO cells, treatedwith 10 μM forskolin, compared to 16). 100% value is defined as effectof 1 μM 16.

FIG. 2A-2J show graphically the effects of nucleoside derivatives onbody temperature (Tb) in WT (C57BL/6J male) or AR-KO mice. Compound 9(FIG. A-E) or 29 (FIG. F-J), both at 3 mg/kg, ip., and vehicle weredosed in wild-type mice (WT, FIGS. 2A and 2F), or mice lacking A₁AR(FIG. 2B, 2G), A₃AR (FIG. C, 2H), or both A₁AR and A₃AR (FIG. 2D, 2I).FIGS. E and J show Tb during the first 60 min after dosing, mean±SEM,N=4 to 12/group. t-Test (2-tailed, paired or unpaired as appropriate) Pvalues for vehicle vs compound, within genotype.

FIG. 3 shows the effect of compounds 9 and 24 on mouse Tb.

FIG. 4A shows the average immobility time in the tail suspension testexhibited by mice treated i.p. with saline (control), 10 mg/kgfluoxetine (FLX), or 0.3 mg/kg of compound 12, 1 mg/kg of compound 12,or 2 mg/kg of compound 12.

FIG. 4B shows the average immobility time in the tail suspension testexhibited by mice treated i.p. with saline (control), 10 mg/kgfluoxetine (FLX), or 3 mg/kg of compound MRS5474, 10 mg/kg of compoundMRS5474, or 20 mg/kg of compound MRS5474.

FIG. 4C shows the structure of MRS5474.

DETAILED DESCRIPTION OF THE INVENTION

In an embod, the invention provides a compound of formula (I):

wherein Y is N or CH,

R¹ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl ordicyclodecylmethyl,

-   -   R² and R⁶ are independently selected from hydrogen, halo, C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆        alkylthio, C₁-C₆ alkoxy, and C₁-C₆ alkylamino;    -   R³ and R⁴ are independently selected from hydrogen, hydroxyl,        amino, mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy        C₁-C₆ alkyl, and hydrazinyl; and    -   R⁵ is selected from hydrogen, hydroxyl, halo, C₁-C₃ alkyl        aminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃        alkyl) aminocarbonyl, C₁-C₃ alkylthio C₁-C₃ alkyl, halo C₁-C₃        alkyl, hydrazinyl, amino C₁-C₃ alkyl, hydroxy C₁-C₃ alkyl, C₃-C₆        cycloalkylamino, hydroxylamino, and C₂-C₃ alkenyl;        or a pharmaceutically acceptable salt thereof.

In an aspect, R⁶ is hydrogen.

In certain aspects, Y is N.

In an aspect, R³ and R⁴ are both hydroxyl.

In certain aspects, R⁵ is selected from hydroxyl and halo.

In certain aspects, R² is H or chloro.

In certain aspects, R¹ is dicyclobutylmethyl.

In certain preferred aspects, the compound is:

In an aspect, the invention provides a compound of formula (II):

wherein Y is N or CH,

R¹⁰ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl anddicyclodecylmethyl, or endo-2-norbornyl,

R¹¹ and R¹⁵ are independently selected from hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy,and C₁-C₆ alkylamino;

R¹² and R¹³ are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; and

R¹⁴ is selected from hydrogen, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylaminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃ alkyl)aminocarbonyl, C₃-C₈ cycloalkyl aminocarbonyl, C₁-C₃ alkylthio C₁-C₃alkyl, C₆-C₁₀ arylthio C₁-C₃ alkyl, halo C₁-C₃ alkyl, hydrazinyl, aminoC₁-C₃ alkyl, hydroxy C₁-C₃ alkyl, C₃-C₆ cycloalkylamino, hydroxylamino,and C₂-C₃ alkenyl, wherein the aryl portion is optionally substitutedwith one or more substituents selected from halo and C₁-C₃ alkoxy;

or a pharmaceutically acceptable salt thereof.

In an aspect, when R¹¹ is chloro and R¹⁴ is hydrogen, R¹⁰ is notdicyclopentylmethyl.

In an aspect, R¹⁵ is hydrogen.

In certain aspects, Y is N.

In an aspect, R¹² and R¹³ are both hydroxyl.

In certain aspects, R¹ is H or chloro.

In an aspect, R¹⁴ is H.

In certain aspects, R¹⁰ is dicyclobutylmethyl

In a particular aspect, the compound is:

In certain aspects, R¹⁴ is halo C₁-C₃ alkyl or hydroxy C₁-C₃ alkyl.

In certain particular aspects, the compound is selected from:

In certain aspects, R¹⁴ is C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylaminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl, or C₃-C₈ cycloalkylaminocarbonyl.

In certain particular aspects, the compound is:

In certain aspects, Y in the compound of formula (II) is CH.

In a particular aspect, the compound is:

In a further aspect, the invention provides a compound of formula (III):

wherein R²⁰ is amino, C₁-C₃ alkoxy, C₁-C₃ alkylamino, hydroxy C₁-C₃alkylamino, di(C₁-C₃ alkyl)amino, or C₃-C₅ cycloalkylamino, and

R²¹ and R²² are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl, or a pharmaceutically acceptable salt thereof.

In an aspect, R²¹ and R²² are both hydroxyl.

In particular aspects, the compound is:

Referring now to terminology used generically herein, the term “alkyl”means a straight-chain or branched alkyl substituent containing from,for example, 1 to about 6 carbon atoms, preferably from 1 to about 4carbon atoms, more preferably from 1 to 2 carbon atoms. Examples of suchsubstituents include methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, and the like.

The term “alkenyl,” as used herein, means a C₂-C₆ alkenyl groupcontaining one or more double bonds.

The term “cycloalkyl,” as used herein, means a cyclic alkyl substituentcontaining from, for example, 4 to about 10 carbon atoms. Examples ofsuch substituents include cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Thecyclic alkyl groups may be unsubstituted or further substituted withalkyl groups such as methyl groups, ethyl groups, and the like.

The term “heterocyclyl,” as used herein, refers to a monocyclic orbicyclic 5- or 6-membered ring system containing one or more heteroatomsselected from the group consisting of O, N, S, and combinations thereof.The heterocyclyl group can be any suitable heterocyclyl group and can bean aliphatic heterocyclyl group, an aromatic heterocyclyl group, or acombination thereof. The heterocyclyl group can be a monocyclicheterocyclyl group or a bicyclic heterocyclyl group. Suitableheterocyclyl groups include morpholine, piperidine, tetrahydrofuryl,oxetanyl, pyrrolidinyl, and the like. Suitable bicyclic heterocyclylgroups include monocylic heterocyclyl rings fused to a C₆-C₁₀ aryl ring.When the heterocyclyl group is a bicyclic heterocyclyl group, both ringsystems can be aliphatic or aromatic, or one ring system can be aromaticand the other ring system can be aliphatic as in, for example,dihydrobenzofuran. The term “heteroaryl” refers to a monocyclic orbicyclic 5- or 6-membered ring system as described herein, wherein theheteroaryl group is unsaturated and satisfies Hickel's rule.Non-limiting examples of suitable heteroaryl groups include furanyl,thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazole,3-methyl-1,2,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl,benzothiazolinyl, and quinazolinyl. The heterocyclyl or heteroaryl groupis optionally substituted with 1, 2, 3, 4, or 5 substituents as recitedherein such as with alkyl groups such as methyl groups, ethyl groups,and the like, halo groups such as chloro, or hydroxyl groups, with arylgroups such as phenyl groups, naphthyl groups and the like, wherein thearyl groups can be further substituted with, for example halo,dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino,substituted amino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,aryloxycarbonyl, thio, alkylthio, arylthio, and the like, wherein theoptional substituent can be present at any open position on theheterocyclyl or heteroaryl group, or with benzo groups, to form a groupof, for example, benzofuran.

The term “alkylcarbonyl,” as used herein, refers to an alkyl grouplinked to a carbonyl group and further linked to a molecule via thecarbonyl group, e.g., alkyl-C(═O)—. The term “alkoxycarbonyl,” as usedherein, refers to an alkoxy group linked to a carbonyl group and furtherlinked to a molecule via the carbonyl group, e.g., alkyl-O—C(═O)—. Theterm “aminocarbonyl,” as used herein, refers to an amino group linked toa carbonyl group and further linked to a molecule via the carbonylgroup, e.g., H₂N—C(═O)—. The term “alkyl aminocarbonyl,” as used herein,refers to an alkylamino group linked to a carbonyl group and furtherlinked to a molecule via the carbonyl group, e.g., alkyl-NH—C(═O)—. Theterm “dialkyl aminocarbonyl,” as used herein, refers to a dialkylaminogroup linked to a carbonyl group and further linked to a molecule viathe carbonyl group, e.g., (alkyl¹)(alkyl²)-NH—C(═O)—. The term“hydroxyalkyl aminocarbonyl,” as used herein, refers to ahydroxyalkylamino group linked to a carbonyl group and further linked toa molecule via the carbonyl group, e.g., HO-alkyl-NH—C(═O)—. The alkylgroups in dialkyl aminocarbonyl can be the same alkyk group or differentalkyl groups. The term “alkylthio alkyl,” as used herein, refers to analkylthio group linked to a second alkyl group and further linked to amolecule via the second alkyl group, e.g., alkyl-S-alkyl-. The terms“alkylthio,” “alkoxy,” and “alkylamino,” as used herein, refer to analkyl group linked to a sulfur atom, oxygen atom, and nitrogen atom,respectively, and further linked to a molecule via the sulfur atom,oxygen atom, and nitrogen atom, e.g., alkyl-S—, alkyl-O—, and alkyl-NH—.

The term “halo” or “halogen,” as used herein, means a substituentselected from Group VIIA, such as, for example, fluorine, bromine,chlorine, and iodine.

The term “aryl” refers to an unsubstituted or substituted aromaticcarbocyclic substituent, as commonly understood in the art, and the term“C₆-C₁₀ aryl” includes phenyl and naphthyl. It is understood that theterm aryl applies to cyclic substituents that are planar and comprise4n+2 π electrons, according to Hickel's Rule.

Whenever a range of the number of atoms in a structure is indicated(e.g., a C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₂-C₁₂, C₂-C₈, C₂-C₆, C₂-C₄alkyl, alkenyl, alkynyl, etc.), it is specifically contemplated that anysub-range or individual number of carbon atoms falling within theindicated range also can be used. Thus, for instance, the recitation ofa range of 1-8 carbon atoms (e.g., C₁-C₈), 1-6 carbon atoms (e.g.,C₁-C₆), 1-4 carbon atoms (e.g., C₁-C₄), 1-3 carbon atoms (e.g., C₁-C₃),or 2-8 carbon atoms (e.g., C₂-C₈) as used with respect to any chemicalgroup (e.g., alkyl, alkylamino, etc.) referenced herein encompasses andspecifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12carbon atoms, as appropriate, as well as any sub-range thereof (e.g.,1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms,1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms,1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbonatoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbonatoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms,4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms,4-10 carbon atoms, 4-11 carbon atoms, and/or 4-12 carbon atoms, etc., asappropriate). Similarly, the recitation of a range of 6-10 carbon atoms(e.g., C₆-C₁₀) as used with respect to any chemical group (e.g., aryl)referenced herein encompasses and specifically describes 6, 7, 8, 9,and/or 10 carbon atoms, as appropriate, as well as any sub-range thereof(e.g., 6-10 carbon atoms, 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbonatoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10carbon atoms, and/or 8-9 carbon atoms, etc., as appropriate).

The phrase “pharmaceutically acceptable salt” is intended to includenontoxic salts synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two.Generally, nonaqueous media such as ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th ed., Mack PublishingCompany, Easton, Pa., 1990, p. 1445, and Journal of PharmaceuticalScience, 66, 2-19 (1977).

Suitable bases include inorganic bases such as alkali and alkaline earthmetal bases, e.g., those containing metallic cations such as sodium,potassium, magnesium, calcium and the like. Non-limiting examples ofsuitable bases include sodium hydroxide, potassium hydroxide, sodiumcarbonate, and potassium carbonate. Suitable acids include inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, maleic acid, tartaric acid, fattyacids, long chain fatty acids, and the like. Preferred pharmaceuticallyacceptable salts of inventive compounds having an acidic moiety includesodium and potassium salts. Preferred pharmaceutically acceptable saltsof inventive compounds having a basic moiety (e.g., a dimethylaminoalkylgroup) include hydrochloride and hydrobromide salts. The compounds ofthe present invention containing an acidic or basic moiety are useful inthe form of the free base or acid or in the form of a pharmaceuticallyacceptable salt thereof.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole.

It is further understood that the above compounds and salts may formsolvates, or exist in a substantially uncomplexed form, such as theanhydrous form. As used herein, the term “solvate” refers to a molecularcomplex wherein the solvent molecule, such as the crystallizing solvent,is incorporated into the crystal lattice. When the solvent incorporatedin the solvate is water, the molecular complex is called a hydrate.Pharmaceutically acceptable solvates include hydrates, alcoholates suchas methanolates and ethanolates, acetonitrilates and the like. Thesecompounds can also exist in polymorphic forms.

In any of the above aspects, the compound or salt of formula (I) canhave at least one asymmetric carbon atom. When the compound or salt hasat least one asymmetric carbon atom, the compound or salt can exist inthe racemic form, in the form of its pure optical isomers, or in theform of a mixture wherein one isomer is enriched relative to the other.In particular, in accordance with the present invention, when theinventive compounds have a single asymmetric carbon atom, the inventivecompounds may exist as racemates, i.e., as mixtures of equal amounts ofoptical isomers, i.e., equal amounts of two enantiomers, or in the formof a single enantiomer. As used herein, “single enantiomer” is intendedto include a compound that comprises more than 50% of a singleenantiomer (i.e., enantiomeric excess up to 100% pure enantiomer).

When the compound or salt has more than one chiral center, the compoundor salt can therefore exist as a mixture of diastereomers or in the formof a single diastereomer. As used herein, “single diastereomer” isintended to mean a compound that comprises more than 50% of a singlediastereomer (i.e., diastereomeric excess to 100% pure diastereomer).

The present invention further provides a pharmaceutical compositioncomprising a compound as described above and a pharmaceuticallyacceptable carrier. The present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective amount, e.g., a therapeutically effective amount, including aprophylactically effective amount, of one or more of the aforesaidcompounds, or salts thereof, of the present invention.

The pharmaceutically acceptable carrier can be any of thoseconventionally used and is limited only by chemico-physicalconsiderations, such as solubility and lack of reactivity with thecompound, and by the route of administration. It will be appreciated byone of skill in the art that, in addition to the following describedpharmaceutical compositions; the compounds of the present invention canbe formulated as inclusion complexes, such as cyclodextrin inclusioncomplexes, or liposomes.

The pharmaceutically acceptable carriers described herein, for example,vehicles, adjuvants, excipients, or diluents, are well known to thosewho are skilled in the art and are readily available to the public. Itis preferred that the pharmaceutically acceptable carrier be one whichis chemically inert to the active compounds and one which has nodetrimental side effects or toxicity under the conditions of use.

The choice of carrier will be determined in part by the particularactive agent, as well as by the particular method used to administer thecomposition. Accordingly, there is a wide variety of suitableformulations of the pharmaceutical composition of the present invention.The following formulations for oral, aerosol, parenteral, subcutaneous,intravenous, intraarterial, intramuscular, interperitoneal, intrathecal,rectal, and vaginal administration are merely exemplary and are in noway limiting.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of the compound dissolved indiluents, such as water, saline, or orange juice; (b) capsules, sachets,tablets, lozenges, and troches, each containing a predetermined amountof the active ingredient, as solids or granules; (c) powders; (d)suspensions in an appropriate liquid; and (e) suitable emulsions. Liquidformulations may include diluents, such as water and alcohols, forexample, ethanol, benzyl alcohol, and the polyethylene alcohols, eitherwith or without the addition of a pharmaceutically acceptablesurfactant, suspending agent, or emulsifying agent. Capsule forms can beof the ordinary hard- or soft-shelled gelatin type containing, forexample, surfactants, lubricants, and inert fillers, such as lactose,sucrose, calcium phosphate, and cornstarch. Tablet forms can include oneor more of lactose, sucrose, mannitol, corn starch, potato starch,alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, calcium stearate, zinc stearate, stearic acid, and otherexcipients, colorants, diluents, buffering agents, disintegratingagents, moistening agents, preservatives, flavoring agents, andpharmacologically compatible carriers. Lozenge forms can comprise theactive ingredient in a flavor, usually sucrose and acacia or tragacanth,as well as pastilles comprising the active ingredient in an inert base,such as gelatin and glycerin, or sucrose and acacia, emulsions, gels,and the like containing, in addition to the active ingredient, suchcarriers as are known in the art.

The compounds of the present invention, alone or in combination withother suitable components, can be made into aerosol formulations to beadministered via inhalation. These aerosol formulations can be placedinto pressurized acceptable propellants, such asdichlorodifluoromethane, propane, nitrogen, and the like. They also maybe formulated as pharmaceuticals for non-pressured preparations, such asin a nebulizer or an atomizer.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.The compound can be administered in a physiologically acceptable diluentin a pharmaceutical carrier, such as a sterile liquid or mixture ofliquids, including water, saline, aqueous dextrose and related sugarsolutions, an alcohol, such as ethanol, isopropanol, or hexadecylalcohol, glycols, such as propylene glycol or polyethylene glycol,glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers,such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acidester or glyceride, or an acetylated fatty acid glyceride with orwithout the addition of a pharmaceutically acceptable surfactant, suchas a soap or a detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils, which can be used in parenteral formulations include petroleum,animal, vegetable, or synthetic oils. Specific examples of oils includepeanut, soybean, sesame, cottonseed, corn, olive, petrolatum, andmineral. Suitable fatty acids for use in parenteral formulations includeoleic acid, stearic acid, and isostearic acid. Ethyl oleate andisopropyl myristate are examples of suitable fatty acid esters. Suitablesoaps for use in parenteral formulations include fatty alkali metal,ammonium, and triethanolamine salts, and suitable detergents include (a)cationic detergents such as, for example, dimethyl dialkyl ammoniumhalides, and alkyl pyridinium halides, (b) anionic detergents such as,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergentssuch as, for example, fatty amine oxides, fatty acid alkanolamides, andpolyoxyethylene-polypropylene copolymers, (d) amphoteric detergents suchas, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazolinequaternary ammonium salts, and (3) mixtures thereof.

The parenteral formulations will typically contain from about 0.5 toabout 25% by weight of the active ingredient in solution. Suitablepreservatives and buffers can be used in such formulations. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain one or more nonionic surfactants having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations ranges from about 5 to about15% by weight. Suitable surfactants include polyethylene sorbitan fattyacid esters, such as sorbitan monooleate and the high molecular weightadducts of ethylene oxide with a hydrophobic base, formed by thecondensation of propylene oxide with propylene glycol. The parenteralformulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, water, for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions can beprepared from sterile powders, granules, and tablets of the kindpreviously described.

The compounds of the present invention may be made into injectableformulations. The requirements for effective pharmaceutical carriers forinjectable compositions are well known to those of ordinary skill in theart. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co.,Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), andASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630(1986).

Topical formulations, including those that are useful for transdermaldrug release, are well-known to those of skill in the art and aresuitable in the context of the invention for application to skin.Topically applied compositions are generally in the form of liquids,creams, pastes, lotions and gels. Topical administration includesapplication to the oral mucosa, which includes the oral cavity, oralepithelium, palate, gingival, and the nasal mucosa. In some aspects, thecomposition contains at least one active component and a suitablevehicle or carrier. It may also contain other components, such as ananti-irritant. The carrier can be a liquid, solid or semi-solid. Inaspects, the composition is an aqueous solution. Alternatively, thecomposition can be a dispersion, emulsion, gel, lotion or cream vehiclefor the various components. In one aspect, the primary vehicle is wateror a biocompatible solvent that is substantially neutral or that hasbeen rendered substantially neutral. The liquid vehicle can includeother materials, such as buffers, alcohols, glycerin, and mineral oilswith various emulsifiers or dispersing agents as known in the art toobtain the desired pH, consistency and viscosity. It is possible thatthe compositions can be produced as solids, such as powders or granules.The solids can be applied directly or dissolved in water or abiocompatible solvent prior to use to form a solution that issubstantially neutral or that has been rendered substantially neutraland that can then be applied to the target site. In aspects of theinvention, the vehicle for topical application to the skin can includewater, buffered solutions, various alcohols, glycols such as glycerin,lipid materials such as fatty acids, mineral oils, phosphoglycerides,collagen, gelatin and silicone based materials.

Additionally, the compounds of the present invention may be made intosuppositories by mixing with a variety of bases, such as emulsifyingbases or water-soluble bases. Formulations suitable for vaginaladministration may be presented as pessaries, tampons, creams, gels,pastes, foams, or spray formulas containing, in addition to the activeingredient, such carriers as are known in the art to be appropriate.

Chemistry

Representative routes to the compounds of the invention are shown inSchemes 1-4.

In certain aspects, the invention provides a method of inducing and/ormaintaining a hypothermic and/or hypometabolic state for treatment of amammal, comprising administering to the mammal an effective amount of acompound of any one of aspects of the invention or a pharmaceuticallyacceptable salt thereof. In certain of these aspects, the mammal hasbeen afflicted with at least one of an anoxic, hypoxic, or hypoperfusionevent. In certain preferred aspects, the anoxic, hypoxic, orhypoperfusion event is selected from birth injury, cardiac arrhythmia,heart attack, cardiac arrest, stroke, brain injury, trauma, and headinjury.

In certain aspects, the invention provides a method of inducing and/ormaintaining a hypothermic and/or hypometabolic state for treatment of amammal, comprising administering to the mammal an effective amount of acompound of any one of aspects of the invention or a pharmaceuticallyacceptable salt thereof, wherein the mammal is, has been, or will besubjected to a surgical procedure. The compound can be administeredbefore, during, or after the surgical procedure. In these aspects, thecompound can be administered as a single dose or in multiple discretedoses at any time before, during, or after the surgical procedure. Inother aspects, the compound can be administered continuously before,during, and after the surgical procedure. Non-limiting examples ofsuitable routes of administration in conjunction with surgicalprocedures include parenteral and/or intrathecal routes ofadministration.

In certain aspects, the invention provides a method of treating adisease or disorder in a mammal in need thereof, wherein the disease ordisorder is selected from chronic pain, acute pain, diabetes, cardiacarrhythmia, myocardial infarction, depression and brain ischemia,comprising administering to the mammal an effective amount of a compoundof any one of aspects of the invention or a pharmaceutically acceptablesalt thereof.

In any of the above aspects, the compound or salt thereof can beadministered parenterally or intrathecally to the mammal. In theseaspects, the compound or salt thereof is preferably administered in theform of a pharmaceutical composition as described herein.

The compounds or salts thereof can be used in any suitable dose.Suitable doses and dosage regimens can be determined by conventionalrange finding techniques. Generally treatment is initiated with smallerdosages, which are less than the optimum dose. Thereafter, the dosage isincreased by small increments until optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. Inproper doses and with suitable administration of certain compounds, thepresent invention provides for a wide range of responses. Typically thedosages range from about 0.001 to about 1000 mg/kg body weight of theanimal being treated/day. For example, in aspects, the compounds orsalts may be administered from about 1 mg/kg to about 1000 mg/kg, fromabout 1 mg/kg to about 500 mg/kg, from about 1 mg/kg to about 300 mg/kg,from about 1 mg/kg to about 100 mg/kg, from about 5 mg/kg to about 100mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about10 mg/kg, from about 120 mg/kg to about 280 mg/kg, from about 140 mg/kgto about 260 mg/kg, from about 150 mg/kg to about 250 mg/kg, or fromabout 160 mg/kg to about 240 mg/kg, of subject body weight per day, oneor more times a day, to obtain the desired therapeutic effect.

The invention includes at least the following aspects.

Exemplary Aspects of Invention

1. A compound of formula (I):

wherein Y is N or CH,

R¹ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl, ordicyclodecylmethyl,

R² and R⁶ are independently selected from hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy,and C₁-C₆ alkylamino;

R³ and R⁴ are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; and

R⁵ is selected from hydrogen, hydroxyl, halo, C₁-C₃ alkyl aminocarbonyl,hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃ alkyl) aminocarbonyl, C₁-C₃alkylthio C₁-C₃ alkyl, halo C₁-C₃ alkyl, hydrazinyl, amino C₁-C₃ alkyl,hydroxy C₁-C₃ alkyl, C₃-C₆ cycloalkylamino, hydroxylamino, and C₂-C₃alkenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of embod 1, wherein R⁶ is hydrogen.

3. The compound or salt of embod 1 or 2, wherein Y is N.

4. The compound or salt of any one of embods 1-3, wherein R³ and R⁴ areboth hydroxyl.

5. The compound or salt of any one of embods 1-4, wherein R⁵ is selectedfrom hydroxyl and halo.

6. The compound or salt of any one of embods 1-5, wherein R² is H orchloro.

7. The compound or salt of any one of embods 1-6, wherein the compoundis:

8. A pharmaceutical composition comprising a compound or salt of any oneof embods 1-7 and a pharmaceutically acceptable carrier.

9. A compound of formula (II):

wherein Y is N or CH,

R¹⁰ is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl,dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl anddicyclodecylmethyl, or endo-2-norbornyl,

R¹¹ and R¹⁵ are independently selected from hydrogen, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy,and C₁-C₆ alkylamino;

R¹² and R¹³ are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; and

R¹⁴ is selected from hydrogen, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkylaminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl, di(C₁-C₃ alkyl)aminocarbonyl, C₃-C₈ cycloalkyl aminocarbonyl, C₁-C₃ alkylthio C₁-C₃alkyl, C₆-C₁₀ arylthio C₁-C₃ alkyl, halo C₁-C₃ alkyl, hydrazinyl, aminoC₁-C₃ alkyl, hydroxy C₁-C₃ alkyl, C₃-C₆ cycloalkylamino, hydroxylamino,and C₂-C₃ alkenyl, wherein the aryl portion is optionally substitutedwith one or more substituents selected from halo and C₁-C₃ alkoxy;

or a pharmaceutically acceptable salt thereof,

with the proviso that when R¹ is chloro and R¹⁴ is hydrogen, R¹⁰ is notdicyclopentylmethyl.

10. The compound or salt of embod 9, wherein R¹⁵ is hydrogen.

11. The compound or salt of embod 9 or 10, wherein Y is N.

12. The compound or salt of any one of embods 9-11, wherein R¹² and R¹³are both hydroxyl.

13. The compound or salt of any one of embods 9-12, wherein R¹ is H orchloro.

14. The compound or salt of any one of embods 9-13, wherein R¹⁴ is H.

15. The compound or salt of embod 14, wherein the compound is:

16. The compound or salt of any one of embods 9-13, wherein R¹⁴ is haloC₁-C₃ alkyl or hydroxy C₁-C₃ alkyl.

17. The compound or salt of embod 16, wherein the compound is selectedfrom:

18. The compound or salt of any one of embods 9-13, wherein R¹⁴ is C₁-C₃alkoxycarbonyl, C₁-C₃ alkyl aminocarbonyl, hydroxy C₁-C₃ alkylaminocarbonyl, or C₃-C₈ cycloalkyl aminocarbonyl.

19. The compound or salt of embod 18, wherein the compound is:

20. The compound or salt of embod 9 or 10, wherein Y is CH.

21. The compound of embod 20, wherein the compound is:

22. A pharmaceutical composition comprising a compound or salt of anyone of embods 9-21 and a pharmaceutically acceptable carrier.

23. A compound of formula (III):

wherein R²⁰ is amino, C₁-C₃ alkoxy, C₁-C₃ alkylamino, hydroxy C₁-C₃alkylamino, di(C₁-C₃ alkyl)amino, or C₃-C₈ cycloalkylamino, and

R²¹ and R²² are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl,

or a pharmaceutically acceptable salt thereof.

24. The compound or salt of embod 23, wherein R²¹ and R²² are bothhydroxyl.

25. The compound or salt of embod 23 or 24, wherein the compound is:

26. A pharmaceutical composition comprising a compound or salt of anyone of embods 23-25 and a pharmaceutically acceptable carrier.

27. A method of inducing and/or maintaining a hypothermic and/orhypometabolic state for treatment of a mammal, comprising administeringto the mammal an effective amount of a compound of any one of embods1-7, 9-21, or 23-25.

28. The method of embod 27, wherein the mammal has been afflicted withat least one of an anoxic, hypoxic, or hypoperfusion event.

29. The method of embod 28, wherein the anoxic, hypoxic, orhypoperfusion event is selected from birth injury, cardiac arrhythmia,heart attack, cardiac arrest, stroke, brain injury, trauma, and headinjury.

30. A method of inducing and/or maintaining a hypothermic and/orhypometabolic state in a mammal, comprising administering to the mammalan effective amount of a compound of any one of embods 1-7, 9-21, or23-25, wherein the mammal is subjected to a surgical procedure.

31. The method of embod 30, wherein the compound is administered before,during, or after the surgical procedure.

32. A method of treating a disease or disorder in a mammal in needthereof, wherein the disease or disorder is selected from chronic pain,acute pain, diabetes, cardiac arrhythmia, myocardial infarction,depression and brain ischemia, comprising administering to the mammal aneffective amount of a compound of any one of embods 1-7, 9-21, or 23-25.

33. The method of any one of embods 27-32, wherein the compound isadministered intrathecally, orally, or parenterally.

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

Materials and Instrumentation

All reagents and solvents were purchased from Sigma-Aldrich (St. Louis,Mo.). ¹H NMR spectra were obtained with a Bruker 400 spectrometer usingCDCl₃, CD₃OD and DMSO as solvents. Chemical shifts are expressed in δvalues (ppm) with tetramethylsilane (δ 0.00) for CDCl₃ and water (δ3.30) for CD₃OD. NMR spectra were collected with a Bruker AVspectrometer equipped with a z-gradient [¹H, ¹³C, ¹⁵N]-cryoprobe. TLCanalysis was carried out on glass sheets precoated with silica gel F254(0.2 mm) from Aldrich. The purity of final nucleoside derivatives waschecked using a Hewlett-Packard 1100 HPLC equipped with a Zorbax SB-Aq 5μm analytical column (50×4.6 mm; Agilent Technologies Inc., Palo Alto,Calif.). Mobile phase: linear gradient solvent system, 5 mM TBAP(tetrabutylammonium dihydrogen phosphate) —CH₃CN from 80:20 to 0:100 in13 min; the flow rate was 0.5 mL/min. Peaks were detected by UVabsorption with a diode array detector at 230, 254, and 280 nm. Allderivatives tested for biological activity showed >95% purity by HPLCanalysis (detection at 254 nm). Low-resolution mass spectrometry wasperformed with a JEOL SX102 spectrometer with 6-kV Xe atoms followingdesorption from a glycerol matrix or on an Agilent LC/MS 1100 MSD, witha Waters (Milford, Mass.) Atlantis C18 column. High resolution massspectroscopic (HRMS) measurements were performed on a proteomicsoptimized Q-TOF-2 (Micromass-Waters) using external calibration withpolyalanine, unless noted. Observed mass accuracies are those expectedbased on known performance of the instrument as well as trends in massesof standard compounds observed at intervals during the series ofmeasurements. Reported masses are observed masses uncorrected for thistime-dependent drift in mass accuracy. All of the reagents werepurchased from Sigma-Aldrich (St. Louis, Mo.), Small Molecules, Inc.(Hoboken, N.J.), Anichem (North Brunswick, N.J.), PharmaBlock, Inc.(Sunnyvale, Calif.), Frontier Scientific (Logan, Utah) and Tractus(Perrineville, N.J.).

Abbreviations:

AR, adenosine receptor; HEK 293, human embryonic kidney 293; DAT, thedopamine transporter; DMF, dimethylformamide; DIPEA,diisopropylethylamine; GPCR, G protein-coupled receptor; HRMS, highresolution mass spectrometry; MD, molecular dynamics; NET, thenorepinephrine transporter; PDSP, NIMH Psychoactive Drug ScreeningProgram; RMSD, root-mean-square deviation; SAR, structure activityrelationship; SERT, the serotonin transporter; Tb, body temperature;TBAF, tetrabutylammonium fluoride; TBAP, tetrabutylammoniumdihydrogenphosphate; TFA, trifluoroacetic acid; THF, tetrahydrofuran;TM, transmembrane; TSPO, the translocator protein.

Example 1

This example demonstrates a method of preparing compounds in accordancewith an aspect of the invention.

(2R,3R,4R,5R)-2-(6-((Dicyclobutylmethyl)amino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(9)

Saturated methanolic ammonia solution (25 mL) was added into thecompound (425 mg, 0.60 mmol) and the solution stirred for overnight attemperature in a sealed tube. Solvent was evaporated and the residue waspurified on flash silica gel column chromatography (CH₂Cl₂:MeOH=25:1) togive the compound 9 (220 mg, 93%) as colorless powder. ¹H NMR (CD₃OD,400 MHz) δ 8.28 (s, 1H), 8.20 (s, 1H), 5.97 (d, J=6.4 Hz, 1H), 4.77 (t,J=5.6 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H), 4.34 (d, J=4.8 Hz, 1H), 4.19 (d,J=6.0 Hz, 1H), 3.92 (d, J₁=2.4 Hz, J₂=12.4 Hz, 1H), 3.78 (d, J₁=2.4 Hz,J₂=12.4 Hz, 1H), 2.55-2.51 (m, 2H), 2.02-1.83 (m, 10H), 1.79-1.75 (m,2H). HRMS calc. C₁₉H₂₈N₅O₄ (M+H)⁺: 390.2141; found 390.2144.

(2S,3S,4R,5R)-2-(Chloromethyl)-5-(6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol(10)

Compound 10 (89%) was prepared from compound 72 following the samemethod as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.27 (s, 1H), 8.24(s, 1H), 6.05 (d, J=5.2 Hz, 1H), 4.79 (d, J=5.2 Hz, 1H), 4.41-4.39 (m,2H), 4.31-4.27 (d, J₁=4.8 Hz, J₂=5.2 Hz, 1H), 3.97 (d, J₁=5.2 Hz, J₂=6.8Hz, 1H), 3.87 (d, J₁=5.2 Hz, J₂=6.8 Hz, 1H), 2.57-2.50 (m, 2H),2.01-1.83 (m, 10H), 1.79-1.75 (m, 2H). HRMS calc. C₁₉H₂₇N₅O₄Cl (M+H)⁺:408.1802; found 408.1800.

(2R,3R,4S,5S)-2-(6-((Dicyclobutylmethyl)amino)-9H-purin-9-yl)-5-((ethylthio)methyl)tetrahydrofuran-3,4-diol(11)

Compound 11 (91%) was prepared from compound 73 following the samemethod as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.30 (s, 1H), 8.23(s, 1H), 6.02 (d, J=5.2 Hz, 1H), 4.78 (t, J=6.0 Hz, 1H), 4.39-4.33 (m,2H), 4.24-4.21 (m, 1H), 3.01 (d, J₁=5.6 Hz, J₂=8.8 Hz, 1H), 2.93 (d,J₁=5.6 Hz, J₂=8.8 Hz, 1H), 2.63-2.48 (m, 4H), 2.01-1.83 (m, 10H),1.76-1.75 (m, 2H), 1.22 (t, J=7.6 Hz, 3H). HRMS calc. C₂₁H₃₂N₅O₃S(M+H)⁺: 434.2226; found 434.2232.

(2R,3R,4R,5R)-2-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(12)

Compound 12 (91%) was prepared from compound 70 following the samemethod as for compound 9. ¹H NMR (CD₃OD, 400 MHz) δ 8.25 (s, 1H), 5.92(d, J=6.0 Hz, 1H), 4.70 (t, J=5.2 Hz, 1H), 4.40-4.32 (m, 2H), 4.17 (d,J=6.8 Hz, 1H), 3.92 (d, J₁=2.4 Hz, J₂=10.0 Hz, 1H), 3.78 (d, J₁=2.4 Hz,J₂=10.0 Hz, 1H), 2.55-2.47 (m, 2H), 2.01-1.84 (m, 10H), 1.77-1.76 (m,2H). HRMS calc. C₁₉H₂₇N₅O₄Cl (M+H)⁺: 424.1752; found 424.1750.

(1R,2R,3S,4R,5S)-4-(6-((Dicyclobutylmethyl)amino)-9H-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol(24)

A solution of compound 60 (30 mg, 0.02 mmol) in methanol (3 mL) and 10%TFA in water (3 mL) was heated at 70° C. for 6 hrs. Solvent wasevaporated under vacuum and the residue was purified on flash silica gelsilica chromatography (CH₂Cl₂:MeOH=25:1) to give the compound 24 (23 mg,86%) as a syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.47 (s, 1H), 8.22 (s, 1H),4.82 (d, J=6.4 Hz, 1H), 4.40 (t, J=6.8 Hz, 1H), 4.31 (d, J=11.6 Hz, 1H),3.91 (d, J=6.4 Hz, 1H), 3.33 (d, J=11.6 Hz, 1H), 2.54-2.50 (m, 2H),1.98-1.83 (m, 10H), 1.76-1.75 (m, 2H), 1.68-1.65 (m, 1H), 1.54 (t, J=5.2Hz, 1H), 0.78-0.75 (m, 1H). HRMS calc. C₂₁H₃₀N₅O₃ (M+H)⁺: 400.2349;found 400.2356.

(1R,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol(25)

Compound 25 (87%) was prepared from compound 61 following the samemethod for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.44 (s, 1H), 4.81 (s,1H), 4.79 (d, J=6.8 Hz, 1H), 4.37 (d, J=8.0 Hz, 1H), 4.29 (d, J=11.6 Hz,1H), 3.90 (d, J=6.4 Hz, 1H), 2.53-2.47 (m, 2H), 1.99-1.88 (m, 10H),1.84-1.82 (m, 2H), 1.65-1.62 (m, 1H), 1.56 (d, J=4.8 Hz, 1H), 0.78-0.75(m, 1H). HRMS calc. C₂₁H₂₉N₅O₃Cl (M+H)⁺: 434.1959; found 434.1964.

(1S,2R,3S,4R,5S)-1-(Chloromethyl)-4-(6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol(26)

Compound 26 (88%) was prepared from compound 63 following the samemethod for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.36 (s, 1H), 8.25 (s,1H), 4.83 (d, J=6.0 Hz, 1H), 4.40 (t, J=7.2 Hz, 1H), 4.33 (d, J=11.6 Hz,1H), 4.01 (d, J=6.4 Hz, 1H), 3.65 (d, J=11.6 Hz, 1H), 2.54-2.51 (m, 2H),1.99-1.83 (m, 10H), 1.79-1.75 (m, 4H), 0.99-0.95 (m, 1H). HRMS calc.C₂₁H₂₉N₅O₂Cl (M+H)⁺: 418.2010; found 418.2016.

(1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-1-(chloromethyl)bicyclo[3.1.0]hexane-2,3-diol(27)

Compound 27 (89%) was prepared from compound 64 following the sameprocedure as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.29 (s, 1H),4.83-4.80 (m, 2H), 4.38 (t, J=8.0 Hz, 1H), 4.31 (d, J=11.6 Hz, 1H), 3.99(d, J=6.8 Hz, 1H), 3.69 (d, J=11.6 Hz, 1H), 2.53-2.47 (m, 2H), 1.99-1.88(m, 10H), 1.84-1.74 (m, 4H), 0.99-0.95 (m, 1H). HRMS calc. C₂₁H₂₈N₅O₂Cl₂(M+H)⁺: 452.1620; found 452.1624.

(1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-1-(((2-fluorophenyl)thio)methyl)bicyclo[3.1.0]hexane-2,3-diol(28)

Compound 28 (90%) was prepared from compound 66 following the sameprocedure as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.13 (s, 1H),7.49-7.45 (m, 1H), 7.20-7.15 (m, 1H), 7.07-7.02 (m, 2H), 4.84 (d, J=6.0Hz, 1H), 4.71 (s, 1H), 4.38 (t, J=7.6 Hz, 1H), 4.05 (d, J=6.8 Hz, 1H),3.69 (d, J=13.6 Hz, 11H), 3.31 (d, J=13.6 Hz, 1H), 2.54-2.48 (m, 2H),2.02-1.89 (m, 10H), 1.84-1.77 (m, 2H), 1.59-1.54 (m, 2H), 0.91-0.87 (m,1H). HRMS calc. C₂₇H₃₂N₅O₂ClSF (M+H)⁺: 544.1949; found 544.1951.

(1R,2R,3S,4R,5S)-4-(6-(((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol(29)

Compound 29 (84%) was prepared from compound 62 following the samemethod for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.44 (s, 1H), 4.80 (s,1H), 4.77 (d, J=6.8 Hz, 1H), 4.29 (d, J=11.6 Hz, 1H), 4.30 (br s, 1H),3.88 (d, J=6.8 Hz, 1H), 3.38 (d, J=11.6 Hz, 1H), 2.35-2.34 (m, 2H),1.93-1.87 (m, 1H), 1.64-1.53 (m, 5H), 1.49-1.34 (m, 2H), 1.27-1.21 (m,2H), 0.78-0.74 (m, 1H). HRMS calc. C₁₉H₂₅N₅O₃Cl (M+H)⁺: 406.1646; found406.1647.

(1S,2R,3S,4R,5S)-4-(6-(((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-1-(chloromethyl)bicyclo[3.1.0]hexane-2,3-diol(31)

Compound 31 (93%) was prepared from compound 65 following the sameprocedure as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.28 (s, 1H),4.81-4.79 (m, 2H), 4.31 (d, J=11.6 Hz, 11H), 4.03 (br s, 11H), 3.97 (d,J=6.8 Hz, 11H), 3.68 (d, J=11.6 Hz, 11H), 2.38-2.32 (m, 2H), 1.92-1.87(m, 1H), 1.82-1.79 (m, 1H), 1.75 (t, J=4.8 Hz, 1H), 1.61-1.55 (m, 3H),1.48-1.34 (m, 2H), 1.30-1.23 (m, 2H), 0.98-0.96 (m, 1H). HRMS calc.C₁₉H₂₄N₅O₂Cl₂ (M+H)⁺: 424.1307; found 424.1314.

9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N-(dicyclobutylmethyl)-9H-purin-6-amine(57)

Dicyclobutylmethylamine (302 mg, 2.17 mmol) and DIPEA (0.75 mL, 4.37mmol) were added to a solution of compound 55 (250 mg, 0.43 mmol) in2-propanol and the solution heated at 75° C. for overnight. Solvent wasevaporated under vacuum and the residue was purified on flash silica gelcolumn chromatography (hexane:ethyl acetate=3:1) to give the compound 57(267 mg, 91%) as a colorless syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.36 (s,11H), 8.19 (s, 11H), 7.67-7.644 (m, 4H), 7.44-7.33 (m, 6H), 5.40 (d,J=7.2 Hz, 11H), 5.04 (s, 11H), 4.72 (d, J=6.8 Hz, 11H), 4.40 (t, J=7.2Hz, 11H), 4.23 (d, J=10.8 Hz, 11H), (d, J=10.8 Hz, 1H), 2.54-2.50 (m,2H), 1.99-1.88 (m, 10H), 1.76-1.75 (m 2H), 1.66-1.65 (m, 1H), 1.51 (s,3H), 1.25 (s, 3H), 1.16 (t, J=4.8 Hz, 1H), 1.10 (s, 9H), 0.92-0.88 (m,1H). HRMS calc. C₄₀H₅₂N₅O₃Si (M+H)⁺: 678.3839; found 678.3832.

9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-chloro-N-(dicyclobutylmethyl)-9H-purin-6-amine(58)

Compound 58 (87%) was prepared from compound 56 following the samemethod for compound 57. ¹H NMR (CD₃OD, 400 MHz) δ 8.27 (s, 1H), 7.66 (d,J=6.8 Hz, 4H), 7.44-7.31 (m, 6H), 5.35 (d, J=7.2 Hz, 1H), 4.95 (s, 1H),4.71 (d, J=7.2 Hz, 1H), 4.39 (t, J=8.0 Hz, 1H), 4.23 (d, J=6.4 Hz, 1H),3.76 (d, J=10.8 Hz, 1H), 2.54-2.50 (m, 2H), 2.01-1.89 (m, 10H),1.83-1.76 (m, 2H), 1.63-1.60 (m, 1H), 1.52 (s, 3H), 1.26 (s, 3H),1.14-1.11 (m, 1H), 1.08 (s, 9H), 0.98-0.93 (m, 1H). HRMS calc.C₄₀H₅₁N₅O₃SiCl (M+H)⁺: 712.3450; found 712.3445.

N-((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[³,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-chloro-9H-purin-6-amine(59)

(1R,2S, 4S)-Bicyclo[2.2.1]nonane (306 mg, 2.75 mmol) and triethylamine(0.76 mL, 5.51 mmol) were added to a solution of compound 56 (336 mg,0.55 mmol) in methanol and the solution stirred at room temperature forovernight. Solvent was evaporated under vacuum and the residue waspurified on flash silica gel column chromatography (hexane:ethylacetate=4:1) to give the compound 59 (319 mg, 82%) as a colorless syrup.1H NMR (CD₃OD, 400 MHz) δ 8.26 (s, 1H), 7.66-7.64 (m, 4H), 7.43-7.32 (m,6H), 5.34 (d, J=6.8 Hz, 1H), 4.95 (s, 1H), 4.69 (d, J=7.2 Hz, 1H), 4.22(d, J=6.8 Hz, 1H), 4.03 (br s, 1H), 3.76 (d, J=6.8 Hz, 1H), 2.36-2.34(m, 2H), 1.94-1.87 (m, 1H), 1.62-1.59 (m, 4H), 1.52 (s, 3H), 1.48-1.36(m, 2H), 1.29-1.24 (m, 5H), 1.12 (t, J=5.2 Hz, 1H), 1.09 (s, 9H),0.98-0.94 (m, 1H). HRMS calc. C₃₈H₄₇N₅O₃SiCl (M+H)⁺: 684.3137; found684.3143.

((3aR,3bR,4aS,5R,5aS)-5-(6-((Dicyclobutylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)methanol(60)

TBAF (0.6 mL, 1M solution in THF) was added to a solution of compound 57(267 mg, 0.39 mmol) in THF and the solution stirred for 1 h at roomtemperature. Solvent was evaporated and the residue was purified onsilica gel column chromatography (CH₂Cl₂:MeOH=30:1) to give the compound60 (161 mg, 93%) as a colorless syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.29(s, 1H), 8.21 (s, 1H), 5.43 (d, J=7.2 Hz, 1H), 5.03 (s, 1H), 4.69 (d,J=7.2 Hz, 1H), 4.40 (t, J=6.4 Hz, 1H), 4.11 (d, J=10.8 Hz, 1H), 3.46 (d,J=10.8 Hz, 1H), 2.55-2.51 (m, 2H), 1.98-1.82 (m, 10H), 1.79-1.76 (m,3H), 1.53 (s, 3H), 1.25 (s, 3H), 1.19 (t, J=5.2 Hz, 1H), 1.00-0.96 (m,1H). HRMS calc. C₂₄H₃₄N₅O₃ (M+H)⁺: 440.2662; found 440.2662.

((3aR,3bR,4aS,5R,5aS)-5-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)methanol(61)

Compound 61 (89%) was prepared from compound 58 following the samemethod for compound 60. ¹H NMR (CD₃OD, 400 MHz) δ 8.22 (s, 1H), 5.39 (d,J=7.2 Hz, 1H), 4.95 (s, 1H), 4.71 (d, J=6.8 Hz, 1H), 4.38 (t, J=8.0 Hz,1H), 4.01 (d, J=11.6 Hz, 1H), 3.63 (d, J=11.6 Hz, 1H), 2.53-2.47 (m,2H), 1.99-1.84 (m, 10H), 1.78-1.69 (m, 3H), 1.52 (s, 3H), 1.26 (s, 3H),1.15 (t, J=4.8 Hz, 1H), 1.00-0.97 (m, 1H). HRMS calc. C₂₄H₃₃N₅O₃Cl(M+H)⁺: 474.2272; found 474.2274.

((3aR,3bR,4aS,5R,5aS)-5-(6-(((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)methanol(62)

Compound 62 (91%) was prepared from compound 59 following the samemethod for compound 60. ¹H NMR (CD₃OD, 400 MHz) δ 8.21 (s, 1H), 5.38 (d,J=6.4 Hz, 1H), 4.95 (s, 1H), 4.69 (d, J=7.2 Hz, 1H), 4.00-3.97 (m, 2H),3.62 (d, J=12.0 Hz, 1H), 2.35-2.33 (m, 2H), 1.99-1.87 (m, 1H), 1.71-1.67(m, 1H), 1.61-1.58 (m, 3H), 1.52 (s, 3H), 1.48-1.33 (m, 2H), 1.31-1.22(m, 5H), 1.14 (t, J=4.8 Hz, 1H), 0.99-0.95 (m, 1H). HRMS calc.C₂₂H₂₉N₅O₃Cl (M+H)⁺: 446.1959; found 446.1953.

9-((3aR,3bS,4aS,5R,5aS)-3b-(Chloromethyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N-(dicyclobutylmethyl)-9H-purin-6-amine(63)

SOCl₂ (0.048 mL, 0.39 mL) was added dropwise to a solution of compound60 (58 mg, 0.13 mmol) in dry CH₃CN at −5° C. followed by pyridine (32 L,0.39 mmol) and the solution stirred for 30 min at same condition. Thenthe reaction mixture was brought to room temperature and stirred forovernight. Water was added into the reaction and the reaction mixturewas neutralized with 1M NaHCO₃ solution. Aqueous layer was extractedwith CH₂Cl₂ (3 times), dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by flash silica gel column chromatography(hexane:ethyl acetate=2:1) to afford the compound 63 (37 mg, 62%) as acolorless syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.39 (s, 1H), 8.37 (s, 1H),5.41 (d, J=7.2 Hz, 1H), 5.09 (s, 1H), 4.83 (d, J=6.8 Hz, 1H), 4.32 (t,J=6.8 Hz, 1H), 3.93 (d, J=10.4 Hz, 1H), 2.64-2.60 (m, 2H), 2.03-1.85 (m,10H), 1.80-1.78 (m, 3H), 1.54 (s, 3H), 1.36 (t, J=5.2 Hz, 1H), 1.27 (s,3H), 1.19-1.15 (m, 1H). HRMS calc. C₂₄H₃₃N₅O₂Cl (M+H)⁺: 458.2323; found458.2322.

2-Chloro-9-((3aR,3bS,4aS,5R,5aS)-3b-(chloromethyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N-(dicyclobutylmethyl)-9H-purin-6-amine(64)

Compound 64 (65%) was prepared from compound 61 following the samemethod for compound 63. ¹H NMR (CD₃OD, 400 MHz) δ 8.15 (s, 1H), 5.38 (d,J=7.2 Hz, 1H), 4.94 (s, 1H), 4.78 (d, J=6.8 Hz, 1H), 4.37 (t, J=8.0 Hz,1H), 4.15 (d, J=11.6 Hz, 1H), 3.79 (d, J=11.6 Hz, 1H), 2.55-2.49 (m,2H), 1.99-1.86 (m, 10H), 1.84-1.74 (m, 3H), 1.53 (s, 3H), 1.30-1.27 (m,4H), 1.14-1.10 (m, 1H). HRMS calc. C₂₄H₃₂N₅O₂Cl (M+H)⁺: 492.1933; found492.1935.

N-((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-2-chloro-9-((3aR,3bS,4aS,5R,5aS)-3b-(chloromethyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-9H-purin-6-amine(65)

Compound 65 (63%) was prepared from compound 62 following the samemethod for compound 63. ¹H NMR (CD₃OD, 400 MHz) δ 8.14 (s, 1H), 5.36 (d,J=7.2 Hz, 1H), 4.94 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.13-4.02 (m, 2H),3.80 (d, J=11.6 Hz, 1H), 2.35-2.33 (m, 2H), 1.92-1.86 (m, 1H), 1.81-1.77(m, 1H), 1.64-1.61 (m, 2H), 1.53 (s, 3H), 1.47-1.33 (m, 2H), 1.30-1.23(m, 7H), 1.14-1.10 (m, 1H). HRMS calc. C₂₂H₂₈N₅O₂Cl₂ (M+H)⁺: 464.1620;found 464.1614.

2-Chloro-N-(dicyclobutylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b-(((2-fluorophenyl)thio)methyl)-2,2-dimethylhexahydrocyclopropa[³,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-9H-purin-6-amine(66)

NaH (5.6 mg, 0.23 mmol) was added portion wise to an ice-cold solutionof 2-fluoro-thiophenol (38 mg, 0.07 mmol) in dry DMF (1 mL). Afterhydrogen evolution completed, compound 64 (29 mg, 0.05 mmol) was addedin dry DMF (0.5 mL) and the solution stirred for overnight at roomtemperature. The reaction mixture was quenched with water and aqueouslayer was extracted with ethyl acetate (3 times), dried over Na₂SO₄,filtered and evaporated. The residue was purified on flash silica gelcolumn chromatography (hexane:ethyl acetate=1:1) to give the compound 66(29 mg, 85%) as a syrup. 1H NMR (CD₃OD, 400 MHz) δ 8.06 (s, 1H),7.52-7.48 (m, 1H), 7.21-7.16 (m, 1H), 7.06-7.00 (m, 2H), 5.36 (d, J=6.8Hz, 1H), 4.81 (s, 1H), 4.79 (d, J=6.8 Hz, 1H), 4.40 (t, J=6.8 Hz, 1H),3.66 (d, J=12.0 Hz, 1H), 3.29 (d, J=12.0 Hz, 1H), 2.53-2.50 (m, 2H),2.02-1.84 (m, 10H), 1.78-1.76 (m, 2H), 1.58-1.52 (m, 1H), 1.52 (s, 3H),1.26 (m, 3H), 1.11 (t, J=5.2 Hz, 1H), 0.97-0.93 (m, 1H). HRMS calc.C₃₀H₃₆N₅O₂CISF (M+H)⁺: 584.2262; found 584.2271.

(2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyldibenzoate (69)

Compound 69 (91%) was prepared from compound 67 following the samemethod for compound 57. ¹H NMR (CD₃OD, 400 MHz) δ 8.26 (s, 1H), 8.08 (s,1H), 8.06-7.93 (m, 6H), 7.64-7.57 (m, 3H), 7.48-7.37 (m, 6H), 6.54-6.49(m, 2H), 6.36 (t, J=5.6 Hz, 1H), 4.92-4.91 (m, 2H), 4.73 (dd, J₁=3.2 Hz,J₂=8.0 Hz, 1H), 4.37 (br s, 1H), 2.55-2.49 (m, 2H), 1.97-1.85 (m, 10H),1.83-1.76 (m, 2H). HRMS calc. C₄₀H₄₀N₅O₇ (M+H)⁺: 702.2928; found702.2919.

(2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(2-chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyldibenzoate (70)

Compound 70 (89%) was prepared from compound 68 following the samemethod for compound 57. ¹H NMR (CD₃OD, 400 MHz) δ 8.21 (s, 1H),8.04-7.94 (m, 6H), 7.63-7.57 (m, 3H), 7.46-7.37 (m, 6H), 6.50 (d, J=4.0Hz, 1H), 6.35-6.28 (m, 2H), 4.75-4.71 (m, 1H), 4.36 (t, J=8.0 Hz, 1H),2.51-2.46 (m, 2H), 1.98-1.87 (m, 10H), 1.82-1.75 (m, 2H). HRMS calc.C₄₀H₃₉N₅O₇Cl (M+H)⁺: 736.2538; found 736.2526.

((3aR,4R,6R,6aR)-6-(6-((Dicyclobutylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(71)

2,2-Dimethoxypropane (0.31 mL, 2.57 mmol) and p-toluenesulfonic acid (97mg, 0.51 mmol) were added to a solution of compound 9 (200 mg, 0.51mmol) in acetone (10 mL) and stirred for 5 h at room temperature.Reaction mixture was neutralized with NaHCO₃, filtered and evaporated.The residue was purified on flash silica gel column chromatography(hexane:ethyl acetate=1:2) to give the compound 71 (211 mg, 96%) as acolorless syrup.

9-((3aR,4R,6S,6aS)-6-(Chloromethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(dicyclobutylmethyl)-9H-purin-6-amine(72)

Compound 72 (67%) was prepared from compound 71 following the samemethod as for compound 63. ¹H NMR (CD₃OD, 400 MHz) δ 8.25 (s, 2H), 6.24(d, J=2.4 Hz, 1H), 5.50 (d, J₁=2.4 Hz, J₂=4.4 Hz, 1H), 5.16 (d, J, =2.4Hz, J₂=6.0 Hz, 1H), 4.45-4.37 (m, 2H), 3.84 (d, J₁=4.4 Hz, J₂=7.2 Hz,1H), 3.70 (d, J₁=4.4 Hz, J₂=7.2 Hz, 1H), 2.54-2.50 (m, 2H), 2.02-1.83(m, 10H), 1.76-1.75 (m, 2H), 1.61 (s, 3H), 1.40 (s, 3H). HRMS calc.C₂₂H₃N₅O₃Cl (M+H)⁺: 448.2115; found 448.2113.

N-(Dicyclobutylmethyl)-9-((3aR,4R,6S,6aS)-6-((ethylthio)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine(73)

Sodium thioethoxide (27.8 mg, 0.33 mmol) was added to a solution ofcompound 72 (37 mg, 0.08 mmol) in dry DMF (1 mL) at 0° C. and thesolution stirred at room temperature for 1 h. The reaction mixture wasquenched with water and the aqueous layer was extracted with ethylacetate (3 times), dried over Na₂SO₄, filtered and evaporated. Theresidue was purified on flash silica gel column chromatography(hexane:ethyl acetate=2:1) to give the compound 73 (34 mg, 87%) as asyrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.26 (s, 1H), 8.25 (s, 1H), 6.19 (d,J=2.4 Hz, 1H), 5.56 (d, J₁=1.6 Hz, J₂=4.8 Hz, 1H), 5.08 (m, 1H),4.39-4.26 (m, 2H), 2.82-2.80 (m, 2H), 2.55-2.46 (m, 4H), 2.01-1.83 (m,10H), 1.77-1.75 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H), 1.14 (t, J=7.2 Hz,3H). HRMS calc. C₂₄H₃₆N₅O₃S (M+H)⁺: 474.2539; found 474.2541.

(1R,2R,3S,4R,5S)-4-(4-(((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)amino)-6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol(30)

A solution of compound 79 (48 mg, 0.07 mmol) in methanol (3 mL) and 10%TFA in water (3 mL) was heated at 70° C. for overnight. Solvent wasevaporated under vacuum and the residue was purified on flash silica gelsilica chromatography (hexane:ethyl acetate=1:2) to give the compound 30(21 mg, 77%) as a syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.18 (s, 1H), 6.87(s, 1H), 5.05 (d, J=11.6 Hz, 1H), 4.63 (s, 1H), 4.53 (d, J=6.4 Hz, 1H),4.29 (d, J=11.6 Hz, 1H), 4.00 (m, 1H), 3.88 (d, J=6.4 Hz, 1H), 2.34-2.33(m, 2H), 2.02-1.98 (s, 1H), 1.92-1.87 (m, 1H), 1.79 (d, J=4.8 Hz, 1H),1.61-1.54 (m, 3H), 1.42-1.35 (m, 2H), 1.26-1.23 (m, 2H), 1.03-0.98 (m,1H). HRMS calculated for C₂₀H₂₆N₄O₃Cl (M+H)+: 405.1693; found 405.1692.

Ethyl(1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxylate(35)

Compound 35 (89%) was prepared from compound 82 following the samemethod as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 7.97 (s, 1H), 5.24(d, J=6.8 Hz, 1H), 4.77 (s, 1H), 4.36 (t, J=8.0 Hz, 1H), 4.28-4.23 (m,2H), 4.11 (d, J=6.4 Hz, 1H), 2.52-2.48 (m, 2H), 2.19-2.16 (m, 1H),1.99-1.82 (m, 11H), 1.77-1.74 (m, 2H), 1.63-1.64 (m, 1H), 1.32 (t, J=7.2Hz, 3H). HRMS calculated for C₂₃H₃₁N₅O₄Cl (M+H)⁺: 476.2065; found476.2068.

(1S,2R,3S,4R,5S)-4-(6-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-N-cyclopropyl-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxamide(36)

Compound 36 (92%) was prepared from compound 75 following the samemethod as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.08 (s, 1H), 5.07(d, J=6.8 Hz, 1H), 4.79 (s, 1H), 4.01-3.99 (m, 2H), 2.77-2.72 (m, 1H),2.34-2.33 (m, 2H), 2.08-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.81 (t, J=4.8Hz, 1H), 1.60-1.51 (m, 3H), 1.47-1.43 (m, 1H), 1.39-1.34 (m, 2H),1.28-1.21 (m, 2H), 0.78-0.77 (m, 2H), 0.67-0.58 (m, 2H). HRMS calculatedfor C₂₂H₂₈N₆O₃Cl (M+H)⁺: 459.1911; found 459.1915.

(1S,2R,3S,4R,5S)-4-(6-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-2,3-dihydroxy-N-(2-hydroxyethyl)bicyclo[3.1.0]hexane-1-carboxamide(37)

Compound 37 (89%) was prepared from compound 76 following the samemethod as for compound 24. ¹H NMR (CD₃OD, 400 MHz) δ 8.05 (s, 1H), 7.76(t, J=5.2 Hz, 1H), 5.01 (d, J=6.4 Hz, 11H), 4.81 (s, 11H), 4.01-3.99 (m,2H), 3.63 (t, J=6.0 Hz, 2H), 3.46 (d, J=5.6 Hz, 2H), 2.35-2.33 (m, 2H),2.12-2.09 (m, 1H), 1.92-1.85 (m, 2H), 1.64-1.52 (m, 3H), 1.48-1.43 (m,1H), 1.39-1.34 (m, 2H), 1.30-1.21 (m, 2H). HRMS calculated forC₂₁H₂₈N₆O₄Cl (M+H)⁺: 463.1861; found 463.1860.

Methyl1-((1S,2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)bicyclo[3.1.0]hexan-2-yl)-1H-1,2,4-triazole-3-carboxylate(39)

Compound 39 (82%) was prepared from compound 80 following the samemethod as for compound 30. ¹H NMR (CD₃OD, 400 MHz) δ 8.09 (s, 1H), 5.57(s, 1H), 4.83 (d, J=6.4 Hz, 1H), 4.13 (d, J=6.4 Hz, 1H), 4.02 (s, 3H),3.94 (d, J=11.6 Hz, 1H), 3.55 (d, J=11.6 Hz, 1H), 1.49-1.43 (m, 2H),0.79-0.76 (m, 1H). HRMS calculated for C₁₁H₁₅N₃O₅Na (M+Na)⁺: 292.0909;found 292.0910.

1-((1S,2R,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)bicyclo[3.1.0]hexan-2-yl)-1H-1,2,4-triazole-3-carboxamide(40)

A solution of compound 39 (15 mg, 0.055 mmol) in saturated methanolicammonia (3 mL) was stirred overnight at room temperature. Solvent wasevaporated and the residue was purified by flash silica gel columnchromatography (CH₂Cl₂:MeOH:Et₃N=20:1:0.1) to give the compound 40 (10mg, 74%) as colorless powder. ¹H NMR (CD₃OD, 400 MHz) δ 7.98 (s, 1H),5.74 (s, 1H), 4.84 (d, J=6.8 Hz, 1H), 4.09 (d, J=6.4 Hz, 1H), 3.95 (d,J=11.6 Hz, 1H), 1.47-1.37 (m, 2H), 0.77-0.74 (m, 1H). HRMS calculatedfor C₁₀H₁₄N₄O₄Na (M+Na)⁺: 277.0913; found 277.0908.

(3aR,3bS,4aS,5R,5aS)-5-(6-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylicacid (74)

TEMPO (9.1 mg, 0.005 mmol) and BAIB (206 mg, 0.64 mmol) were added to asolution of compound 62 (130 mg, 0.29 mmol) in CH₃CN (2 mL) and water (2mL) and stirred for 3 days at room temperature. The aqueous layer wasextracted with ethyl acetate (3 times), dried (Na₂SO₄), filtered andevaporated under vacuum. The crude mixture was purified on flash silicagel column chromatography (CH₂Cl₂:MeOH=30:1) to give the compound 74 (70mg, 53%) as a syrup. ¹H NMR (CD₃OD, 400 MHz) δ 8.02 (s, 1H), 5.85 (d,J=6.8 Hz, 1H), 4.98 (s, 1H), 4.81 (d, J=7.2 Hz, 1H), 4.02 (br s, 1H),2.35-2.33 (m, 2H), 2.25-2.21 (m, 1H), 1.92-1.87 (m, 1H), 1.70-1.67 (m,1H), 1.61-1.58 (m, 2H), 1.54-1.51 (m, 5H), 1.47-1.35 (m, 2H), 1.28-1.21(m, 5H). HRMS calculated for C₂₂H₂₇N₅O₃Cl (M+H)⁺: 444.1802; found444.1809.

(3aR,3bS,4aS,5R,5aS)-5-(6-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-N-cyclopropyl-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide(75)

Cyclopropylamine (6.3 μL, 0.09 mmol), HATU (38 mg, 0.1 mmol) and DIPEA(0.17 mL, 0.1 mmol) were added to a solution of compound 74 (35 mg, 0.07mmol) in dry DMF (1 mL) and stirred for overnight at room temperature.Solvent was evaporated under vacuum and the residue was purified onflash silica gel column chromatography (hexane:ethyl acetate=1:1) togive the compound 75 (28 mg, 72%) as syrup. ¹H NMR (CD₃OD, 400 MHz) δ8.05 (s, 1H), 5.76 (d, J=7.2 Hz, 1H), 4.94 (s, 1H), 4.84 (d, J=7.2 Hz,1H), 4.01 (br s, 1H), 2.72-2.68 (m, 1H), 2.34-2.32 (m, 2H), 2.16-2.12(m, 1H), 1.91-1.86 (m, 1H), 1.60-1.53 (m, 6H), 1.46-1.36 (m, 2H),1.34-1.23 (m, 6H), 0.76-0.73 (m, 2H), 0.67-0.61 (m, 2H). HRMS calculatedfor C₂₅H₃₂N₆₀₃Cl (M+H)⁺: 499.2224; found 499.2218.

(3aR,3bS,4aS,5R,5aS)-5-(6-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloro-9H-purin-9-yl)-N-(2-hydroxyethyl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide(76)

Compound 76 (70%) was prepared from compound 74 following the samemethod as for compound 75. ¹H NMR (CD₃OD, 400 MHz) δ 8.06 (s, 1H), 5.78(d, J=7.2 Hz, 1H), 4.97 (s, 1H), 4.84 (d, J=7.2 Hz, 1H), 4.01 (br s,1H), 3.67 (t, J=6.0 Hz, 2H), 3.53-3.47 (m, 2H), 2.35-2.32 (m, 2H),2.18-2.14 (m, 1H), 1.92-1.87 (m, 1H), 1.61-1.54 (m, 6H), 1.48-1.47 (m,1H), 1.43-1.41 (m, 2H), 1.38-1.32 (m, 1H), 1.30-1.24 (m, 5H). HRMScalculated for C₂₄H₃₁N₆O₄Cl (M+H)⁺: 503.2095; found 503.2048.

1-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-4,6-dichloro-1H-imidazo[4,5-c]pyridine(78)

DIAD (0.14 mL, 0.70 mmol) was added to a solution of3-deaza-2,6-dichloropurine (134 mg, 0.70 mmol) and triphenylphosphine(186 mg, 0.70 mmol) in THF (3 mL) at 0° C. and the mixture was stirredfor 20 minutes at room temperature. A solution of compound 77 (156 mg,0.35 mmol) in THF (2 mL) was added into the reaction mixture and stirredfor overnight at room temperature. Solvent was evaporated and theresidue was purified on flash silica gel column chromatography(hexane:ethyl acetate=5:1) to give the compound 78 (109 mg, 50%) ascolorless foamy solid. 1H NMR (CD₃OD, 400 MHz) δ 8.54 (s, 1H), 7.98 (s,1H), 7.71-7.66 (m, 4H), 7.46-7.36 (m, 6H), 5.35 (d, J=6.4 Hz, 1H), 5.01(s, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.23 (d, J=11.2 Hz, 1H), 3.59 (d,J=11.2 Hz, 1H), 1.86-1.83 (m, 1H), 1.52 (s, 3H), 1.29 (s, 3H), 1.21 (t,J=5.2 Hz, 1H), 1.13 (s, 9H), 0.97-0.94 (m, 1H). HRMS calculated forC₃₂H₃₆N₃O₃Cl₂Si (M+H)⁺: 608.1903; found 608.1896.

N-((1R,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-1-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[³,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-4-amine(79)

(1R,2S, 4S)-Bicyclo[2.2.1]nonane (105 mg, 0.9 mmol) and DIPEA (0.31 mL,1.8 mmol) were added to a solution of compound 78 (109 mg, 0.18 mmol) in2-propanol and heated at 130° C. for 6 hours under microwave condition.Solvent was evaporated under vacuum and the residue was purified onflash silica gel column chromatography (hexane:ethyl acetate=4:1) togive the compound 79 (89 mg, 73%) as a colorless syrup. ¹H NMR (CD₃OD,400 MHz) δ 8.54 (s, 1H), 7.73-7.68 (m, 4H), 7.47-7.37 (m, 6H), 6.79 (s,1H), 5.35 (d, J=7.2 Hz, 1H), 4.83 (s, 1H), 4.58 (d, J=7.2 Hz, 1H), 4.25(d, J=7.2 Hz, 1H), 4.01-3.98 (m, 1H), 3.49 (d, J=7.2 Hz, 1H), 2.37-2.32(m, 2H), 1.92-1.87 (m, 1H), 1.83-1.80 (m, 1H), 1.61-1.57 (m, 3H), 1.52(s, 3H), 1.43-1.35 (m, 2H), 1.27-1.23 (m, 5H), 1.18 (t, J=4.8 Hz, 1H),1.19 (s, 9H), 0.92-0.89 (m, 1H). HRMS calculated for C₃₉H₄₈N₄O₃C₁₂Si(M+H)⁺: 683.3184; found 683.3179.

Methyl1-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-1H-1,2,4-triazole-3-carboxylate(80)

Compound 80 (68%) was prepared from compound 77 following the samemethod as for compound 78. ¹H NMR (CD₃OD, 400 MHz) δ 8.02 (s, 1H),7.64-7.61 (m, 4H), 7.44-7.32 (m, 6H), 5.72 (s, 1H), 5.27 (d, J=6.8 Hz,1H), 4.88 (s, 1H), 4.01-3.99 (m, 4H), 3.63 (d, J=10.8 Hz, 1H), 1.52 (s,3H), 1.46-1.43 (m, 1H), 1.25 (s, 3H), 1.10-1.04 (m, 10H), 0.83-0.79 (in,1H). HRMS calculated for C₃₀H₃₈N₃O₅Si (M+H)⁺: 548.2581; found 548.2574.

Ethyl(3aR,3bS,4aS,5R,5aS)-5-(2-Chloro-6-((dicyclobutylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate(82)

Compound 82 (85%) was prepared from compound 81 following the samemethod as for compound 57. ¹H NMR (CD₃OD, 400 MHz) δ 8.04 (s, 1H), 5.86(d, J=7.2 Hz, 1H), 4.97 (s, 1H), 4.82 (d, J=7.2 Hz, 1H), 4.36 (t, J=8.0Hz, 1H), 4.29-4.20 (m, 2H), 2.52-2.48 (m, 2H), 2.28-2.24 (m, 1H),1.90-1.87 (m, 10H), 1.77-1.71 (m, 2H), 1.68-1.64 (m, 1H), 1.55-1.52 (m,4H), 1.33 (t, J=7.2 Hz, 3H), 1.28 (s, 3H). HRMS calculated forC₂₆H₃₅N₅O₄Cl (M+H)⁺: 516.2299; found 516.2246.

Example 2

This example demonstrates binding affinities of adenosine receptor (AR)ligands to the compounds indicated, including reference compounds 1-7and 15-18.

Binding was determined in membranes of CHO or HEK293 (A_(2A) only) cellsstably expressing one of three hAR subtypes, unless noted (n=3-5). Thebinding affinity for hA₁, A_(2A) and A₃ARs was expressed as K_(i) valuesusing agonists [³H]N⁶—R-phenylisopropyladenosine 51,[³H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine52, or [¹²⁵I]N⁶-(4-amino-3-iodobenzyl)adenosine-5′-N-methyluronamide 53,respectively. A percent in italics refers to inhibition of binding at 10μM. Nonspecific binding was determined using adenosine5′-N-ethyluronamide 54 (10 μM). Values are expressed as the mean±SEM(n=3, unless noted). K_(i) values were calculated as reported.⁴²Off-target interactions determined by the PDSP. Receptor abbreviationsas as follows: serotonin receptors (5HTRs); dopamine receptors (DRs);rat brain benzodiazepine receptors (BZP); GABA receptors, dopaminetransporter (DAT); norepinephrine transporter (NET); TSPO (translocatorprotein); adrenergic receptors (α- and β-); muscarinic receptors (MRs);delta (DOR), kappa (KOR), and mu (MOR) opioid receptors; sigma receptors(σ); and histamine receptors (HRs). Gp, guinea pig.

TABLE 1 Adenosine Receptor Binding for Ribose Analogs

Off- A₁AR target, % receptor inhibition A_(2A)AR A₃AR (h, unless orK_(i) % % inhibition noted) Cmpd R¹ R² R³ (nM)^(a) inhibition^(a) orK_(i) (nM)^(a) (K_(i), μM)^(a) 1a^(c,d)

H OH 2.3 (h), 0.22 ± 0.01 (m) 794 (h), 808 ± 89 (m) 72 ± 12 (h), 534 ±14 (m) ND 2^(c,d)

Cl OH 0.83 (h), 0.21 ± 0.10 (m) 2270 (h), 988 (m) 38 ± 6 (h), 17 ± 5 (m)ND 5^(f)

H 2-F—Ph 12 (h) >10,000 (h) >1000 (h) ND 8^(b)

H OH 0.85 ± 0.27 (h), 0.8 (r) 1470 ± 380 (h), 1370 (r) 41.3 ± 5.3 (h)none 9

H OH 2.14 ± 0.52 (h), 0.37 ± 0.02 (m) 3550 ± 440 (h) 10,600 ± 1400 (h),897 ± 45 (m) DAT 1.78, NET 4.82 10

H Cl 4.90 ± 0.87 (h), 0.71 ± 0.12 (m) 5200^(i) (h) 16,600 ± 2000 (h),2110 ± 50 (m) TSPO 3.98, σ₁ 0.69, σ₂ 0.662 11

H —SEt 63.4 ± 12.1 (h), 3.58 ± 0.01 (m) 30 ± 5% (h) 6220 ± 1480 (h), 718± 150 (m) TSPO (90% inhib.^(j)) σ₁ 0.626, σ₂ 0.642 12

Cl OH 17.8 ± 8.7 (h), 0.65 ± 0.06 (m) 2550 ± 540 (h) 13,200 ± 2500 (h),653 ± 85 (m) 5HT_(2C) 1.45 3^(c,d)

H Cl 0.38 ± 0.19 (h), 0.34 (r), 0.14 ± 0.02 (m) >10,000 (h), 477 (r) 915± 299 (h), 282 (r), 424 ± 41 (m) ND 4^(c)

H C1 0.51 (h), 0.20 ± 0.01 (m) 1340 (h), 3990 ± 360 (m) 1290 (h), 2410 ±330 (m) ND 13^(c)

H 0.76 ± 0.42 (h) 2050 ± 570 (h) 355 ± 117 (h), 1560 ± 140 (m) σ₁ 0.484,σ₂ 0.432, 5HT₇ 1.24

TABLE 2 Adenosine Receptor Binding for Ribose Analogs

Off- target, A₁AR A₃AR receptor % % (h, inhi- A_(2A)AR inhi- unlessbition % bition noted) or K_(i) inhi- or K_(i) (K_(i), Cmpd R¹ R² R⁴(nM)^(a) bition^(a) (nM)^(a) μM)^(a) 14 H H OH 24 ± 4% 11 ± 4% 32 ± BZP(r) (h) (h) 9% (h) 7.34, σ₁ 1.48, σ₂ 0.796 15^(d) H H NHMe 36.7 ± 466 ±95 24.4 ± none 9.4 (h), (h), 7.9 (h), 84 (r) 67 (r) 63 (r) 16^(c,d,b) HH NHEt 6.8 ± 2.4 2.2 ± 0.6 35 ± none (h),g (h),g 12 (h), 3.00 ± 35.0 ±14.1 ± 0.10 (h), 14.0 (h), 6.8(m), 0.45 ± 12 (r) 113 (r) 0.13 (m), 63(r) 17^(c,d) H H NH-c-Pr 1.90 ± 50 ± 10 180 ± 50 H₁ 7.88, 0.60 (h), (h),(h), σ₁ 4.12 6.4 (r) 13.4 (r) 1600 (r) (gp), σ₂ 4.35 18^(d,h) H HNH(CH₂)₂OH 12.8 ± 505 ± 30 9450 ± ND 3.1 (h) (h) 1760 (h)

TABLE 3 Adenosine Receptor Binding for “Truncated” Methanocarba Analogs

Off- target, A₃AR receptor A₁AR % (h, % inhi- unless inhibition A_(2A)ARbition noted) or K_(i) % or K_(i) (K_(i), Cmpd R¹ R² (nM)^(a)inhibition^(a) (nM)^(a) μM)^(a) 7^(c)

C1 47.9 ± 10.5 (h), 5.20 ± 0.05 (m) 3950 ± 410 (h), 34 ± 9% (m) 470 ± 15(h), 1060 ± 250 (m) 5HT_(2B) 0.641, 5HT_(2C) 1.85 19

Cl 961 ± 639 (h) 46 ± 6% (h) 822 ± 449 (h), 385 ± 52 (m) 5HT_(2B) 2.90,5HT_(2C) 8.32, α_(2A) 6.96, TSPO 2.38 29^(c)

Cl 34 ± 3% (h) 13 ± 3% (h) 48 ± 2% (h) 5HT_(2C) 2.92, σ₁ 5.09, σ₂ 2.01

TABLE 4 Adenosine Receptor Binding for Hydroxymethyl and ChloromethylMethanocarba Analogs

Off- A₁AR A₃AR target, % % receptor inhibition A_(2A)AR inhibition (h,unless or K_(i) % or K_(i) noted) Cmpd R¹ R² R³ (nM)^(a) inhibition^(a)(nM)^(a) (K_(i), μM)^(a) 21^(b) H Cl OH 105 ± 63 3420 ± 270 353 ± 54none (h), (h), 1910 (h)^(d) 273 (r)^(b) (r)^(b) 22 H Cl Cl 7.61 ± 0.731750 ± 290 253 ± 148 σ₁ 1.97, (h) (h) (h) σ₂ 2.55 23^(b)

Cl 39 ± 17 (h), 0.71 ± 0.06 (m) 2200 (h), 41 ± 9% (m) 1600 ± 210 (h),1030 ± 40 (m) 5HT_(2B) 0.641, 5HT_(2C) 1.85, DAT 4.75 24

H 22.7 ± 3.0 (h), 0.53 ± 0.19 (m) 34 ± 1% (h), 51 ± 6% (h), 918 ± 21 (m)BZP (r) 4.08, 5HT_(2B) 0.214, 5HT_(2C) 1.32, σ₁ 1.79, σ₂ 0.753 25

Cl 8.96 ± 1.02 (h), 2.47 ± 0.26 (m) 55 ± 5% (h), 26 ± 3% (m) 25 ± 2%(h), 612 ± 58 (m) 5HT_(2B) 0.153, 5HT_(2C) 0.238, M₅ 3.00, DAT 4.75 TSPO2.93 26

H Cl 32.7 ± 12.4 (h), 1.05 ± 0.19 (m) 38 ± 3% (h) 49 ± 4% (h), 934 ± 18(m) 5HT_(2B) 2.01, α_(2A) 6.80, σ₁ 1.50, σ₂ 1.17, TSPO, 2.02 27

Cl Cl 120 ± 23 (h), 11.2 ± 0.8 (m) 17 ± 24% (h), 20 ± 3% (m) 3820 ± 1820(h), 1560 ± 60 (m) 5HT_(2B) 1.52, 5HT_(2C) 1.75, H₂ 2.60, σ₂ 0.349,TSPO, 2.89 28

Cl S—(2-F—Ph) 45 ± 4% (h), 2490 ± 280 (m) 22 ± 5% (h), 20 ± 9% (m) 9750± 4030 (h), 7440 ± 660 (m) 5HT_(2B) 0.334, 5HT_(2C) 1.46, σ₂ 0.583 29

Cl OH 23.6 ± 5.2 (h), 1.05 ± 0.03 (m) 4260^(i) (h), 15 ± 2% (m) 288 ± 54(h), 574 ± 23 (m) 5HT_(2B) 0.472, NET 5.74 30 (Y = N)

Cl OH 240 ± 19 (h) 29 ± 13% (h) 145 ± 74 (h) none 31

Cl Cl 44.8 ± 1.3 (h), 1.86 ± 0.10 (m) 54 ± 8% (h), 15 ± 1% (m) 456 ± 201(h), 503 ± 13 (m) none

TABLE 5 Adenosine Receptor Binding for Ester and Amido MethanocarbaAnalogs

Off- target, receptor A₁AR A₃AR (h, % % unless inhibition A_(2A)ARinhibition noted) or K_(i) % or K_(i) (K_(i), Cmpd R¹ R² R⁴ (nM)^(a)inhibition^(a) (nM)^(a) μm)^(a) 32^(b)

Cl OEt 360 ± 74 (h) 1570 ± 180 (h) 236 ± 41 (h) 5HT_(2B) 0.015, 5HT_(2C)0.054, TSPO 2.50 33^(b) (2′,3′- C(Me₃)₂ (see below)

Cl OEt 49 ± 9% (h) 15 ± 2% (h) 41 ± 6% (h) 5HT_(5A) 8.69, H₂ 6.38 34^(b)

Cl NHMe 110 ± 14 (h) 4320 ± 1870 (h) 34 ± 11 (h) 5HT_(2B) 0.023,5HT_(2C) 0.749 35

Cl OEt 73.8 ± 14.2 (h) 57 ± 12% (h) 1160 ± 300 (h) 5HT_(2B) 0.097,5HT_(2C) 0.089, M₃ 5.90, σ₂ 2.02 6e

Cl NHMe 18.3 ± 6.3 (h), 0.68 ± 0.02 (m) 3250 ± 300 (h) 3.7 ± 0.9 (h),5.8 ± 1.6 (r), 5HT_(2B) 0.012, σ₁ 1.55 3.46 ± 0.13 (m) 36

Cl NH-c-Pr 1.22 ± 0.05 (h), 0.45 ± 0.03 (m) 520 ± 119 (h), 2650 ± 560(m) 59.0 ± 17.8 (h), 29.5 ± 0.6 (m) 5HT_(2B) 1.57 37

Cl NH(CH₂)₂OH 17.6 ± 5.3 (h), 1.56 ± 0.09 (m) 5400^(i) (h), 23 ± 1% (m)127 ± 29 (h), 447 ± 43 (m) 5HT_(2B) 0.718, KOR, 2.63

TABLE 6 Purine Methanocarba Analogs

A₃AR Off-target, A₁AR A_(2A)AR % receptor (h, % inhibition % inhibitionunless noted) Cmpd R¹ or K_(i) (nM)^(a) inhibition^(a) or K_(i) (nM)^(a)(K_(i), μM)^(a) 38^(g)* — 7410 ± 100 23 ± 6% (h) 16 ± 5% ND (ribavirin)(h) (h) 39 OMe 6 ± 4% (h), 14 ± 5% (h) 22 ± 4% β₃ 1.42, 2990 ± 80 (h),H₃ 4.52, (m) 15 ± 2% σ₂ 1.72 (m) 40 NH₂ 495 ± 35 11 ± 3% (h) 41 ± 6%5HT_(2B) 1.91, (h), (h), 5HT_(2C) 2.35, 25.2 ± 2.8 47 ± 2% DAT 6.61, (m)(m) σ₂ 2.09*Ribavirin structure:

Example 3

This example demonstrates the functional activity of selected nucleosidederivatives (% E_(max) at 10 μM) at mA₁AR and mA₃AR in a guaninenucleotide binding assay.

cLogP was calculated using ChemDraw Professional, v. 16.0. Bindingselectivity for mA1Ar is expressed in terms of fold, compared to mA₃AR(Data from Table 1). E_(max) at the mA3AR is expressed as the mean(effect of 10 μM of test compound as a % of 10 μM 16)±SEM in increasingAR-mediated [³⁵S]GTPγS binding, n=3-6. ND, not determined.

TABLE 7 Guanine Nucleotide Binding Assay Binding K_(i)(and Compoundselectivity) E_(max), E_(max), (MW, cLogP) for mA₁AR mA₁AR, %^(c) mA₃AR,% 9 0.37 nM 101 ± 7 70 ± 9 (389, −7.70) (2420) 12 0.65 nM  90 ± 19 63 ±5 (424, −0.39) (1000) 24 0.53 nM  97 ± 11 92 ± 3 (400, −7.62) (1730) 291.05 nM 104 ± 6 62 ± 5 (406, 1.18) (547) 31 1.86 nM  123 ± 16  50 ± 11(424, 2.38) (270) 40 25.2 nM ND 31 ± 3 (254, −4.52) (−400)

Example 4

This example demonstrates hypothermia and locomotor activity parametersin wild-type C57BL/6J mice.

Compounds were dosed ip. Tb and activity were measured by telemetry andthe averages from dosing to 60 min were calculated. P value >0.05 wasconsidered not significant (ns). Data are for the highest dose used andare mean±SD from 3 to 22 mice/group (usually 5-7). P values are unpairedt-Test vs vehicle-treated controls assayed simultaneously. Vehicle dataare mean±SD from all (n=83) vehicle treated mice.

TABLE 8 Hypothermia and Locomotor Activity Parameters Dose Tb TbActivity Activity ARs causing Compound (mg/kg) (° C.) P value (counts) Pvalue hypothermia Vehicle 36.3 ± 0.8 15.5 ± 5.5 1 1 32.4 ± 0.5 <0.0001 1.5 ± 0.5 0.0078 A₃AR > A₁AR³⁰ 4 3 32.2 ± 1.3 0.0014  2.8 ± 1.6 0.0055A₁AR > A₃AR³⁰ 7 3 33.4 ± 1.7 <0.0001  5.5 ± 4.1 <0.0001 A₃AR >> A₁AR³⁰ 93 33.0 ± 0.7 <0.0001  6.6 ± 2.3 <0.0001 A₁AR selective (FIG. 2) 10 1035.8 ± 0.1 ns 20.5 ± 4.6 ns 12 3 35.5 ± 0.8 0.047 13.5 ± 3.5 ns 24 336.2 ± 0.4 ns 18.1 ± 6.8 ns 25 10 36.6 ± 0.2 ns 18.4 ± 3.2 ns 26 3 35.9± 0.5 ns 14.8 ± 1.7 0.041 27 10 36.5 ± 0.6 ns  18.9 ± 10.2 ns 29 3 33.4± 0.7 <0.0001 10.0 ± 4.3 0.046 A₃AR > A₁AR  31 3 36.6 ± 0.5 0.055 16.8 ±3.6 0.040 40 10 35.7 ± 0.7 ns 19.1 ± 5.3 ns

Example 5

This example demonstrates plasma protein binding at 10 μM in threespecies.

Plasma protein binding in human plasma, mouse plasma, and rat plasma wasdetermined. Verapamil and warfarin served as positive controls. Theresults are expressed as unbound percent±standard deviation. Forcompound 40, the plasma protein binding was estimated as >80% free. Theresults are set forth in Table 9.

TABLE 9 Plasma Protein Binding human, mouse, rat, Compound % free^(b) %free^(b) % free^(b) 9 6.05 ± 1.60 20.6 ± 1.2  14.6 ± 0.01 12 5.81 ± 0.394.74 ± 0.67 4.64 ± 0.06 24 14.6 ± 1.3  27.5 ± 1.7  17.8 ± 1.2  29 9.75 ±2.03 7.68 ± 0.39 6.59 ± 0.49 31 4.04 ± 0.60 2.95 ± 0.84 2.53 ± 0.45 40 cc c

Example 6

This example demonstrates the average core body temperature (Tb) of micedosed with compounds 9 and 24, in accordance with an aspect of theinvention.

Mice were dosed with 0.052 mg/kg and with 0.157 mg/kg of compounds 9 and24. The average Tb was measured after 120 min. The results are shown inFIG. 3.

As is apparent from the results shown in FIG. 3, administration ofcompounds 9 and 24 resulted in robust decreases in Tb in mice after 120min.

Example 7

This example demonstrates the effect of compound 12 on the immobilitytime exhibited by mice in the tail suspension test as compared withfluoxetine, a known anti-depressant drug, in accordance with an aspectof the invention.

A first set of five groups of 8 mice were treated with saline (control),or treated with 10 mg/kg of fluoxetine, 0.3 mg/kg of compound 12, 1mg/kg of compound 12, or 2 mg/kg of compound 12 by i.p. administration.1 hour after administration of compounds, the mice were individuallysuspended by their tails for 6 minutes, and the average amount of timethe mice were immobile was determined. The immobility times are setforth in FIG. 4A. A second set of five groups of 8 mice were untreated(control), or treated with 10 mg/kg of fluoxetine, 3 mg/kg ofcomparative compound MRS5474, 10 mg/kg of compound MRS5474, or 20 mg/kgof compound MRS5474 by i.p. administration. 1 hour after administrationof compounds, the mice were individually suspended by their tails for 6minutes, and the average amount of time the mice were immobile wasdetermined. The immobility times are set forth in FIG. 4B. The structureof compound MRS5474 is shown in FIG. 4C.

As is apparent from the results shown in FIGS. 4A and 4B, mice treatedwith 0.3 mg/kg of compound 12 exhibited an average immobility time inthe tail suspension test that was approximately ⅔ of the averageimmobility time exhibited by mice treated with 10 mg/kg of fluoxetine,and approximately ½ of the average immobility time exhibited by thecontrol group of mice. Mice treated with 3 mg/kg, 10 gm/kg, or 20 mg/kgof MRS5474 exhibited average immobility times that were lower than theaverage immobility times exhibited by the control group of mice, butwere approximately twice longer than the average immobility timesexhibited by mice treated with fluoxetine.

Example 8

This example demonstrates the stability of compound 12 in simulatedgastric fluid, in accordance with an aspect of the invention.

Compound 12 and MRS5474 (comparative) were kept in simulated gastricfluid at a pH of 1.60 and a temperature of 37° C. After 120 min, 100% ofthe initial amount of compound 12 was present in the fluid while 51% ofthe initial amount of MRS5474 was present in the fluid.

REFERENCES

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All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embods of this invention are described herein, including thebest mode known to the inventors for carrying out the invention.Variations of those preferred s may become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

1-33. (canceled)
 34. A compound of formula (I), (II), or (III):

wherein: in formula (I): Y is N or CH, R¹ is dicyclobutylmethyl,dicyclopentylmethyl, dicyclohexylmethyl, dicycloheptylmethyl,dicyclooctylmethyl, dicyclononylmethyl, or dicyclodecylmethyl, R² and R⁶are independently selected from hydrogen, halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy, andC₁-C₆ alkylamino; R³ and R⁴ are independently selected from hydrogen,hydroxyl, amino, mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxyC₁-C₆ alkyl, and hydrazinyl; and R⁵ is selected from hydrogen, hydroxyl,halo, C₁-C₃ alkyl aminocarbonyl, hydroxy C₁-C₃ alkyl aminocarbonyl,di(C₁-C₃ alkyl) aminocarbonyl, C₁-C₃ alkylthio C₁-C₃ alkyl, halo C₁-C₃alkyl, hydrazinyl, amino C₁-C₃ alkyl, hydroxy C₁-C₃ alkyl, C₃-C₆cycloalkylamino, hydroxylamino, and C₂-C₃ alkenyl; in formula (II): Y isN or CH, R¹⁰ is dicyclobutylmethyl, dicyclopentylmethyl,dicyclohexylmethyl, dicycloheptylmethyl, dicyclooctylmethyl,dicyclononylmethyl, dicyclodecylmethyl, or endo-2-norbornyl, R¹¹ and R¹⁵are independently selected from hydrogen, halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, heteroaryl, C₁-C₆ alkylthio, C₁-C₆ alkoxy, andC₁-C₆ alkylamino; R¹² and R¹³ are independently selected from hydrogen,hydroxyl, amino, mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxyC₁-C₆ alkyl, and hydrazinyl; and R¹⁴ is selected from hydrogen, C₁-C₃alkoxycarbonyl, C₁-C₃ alkyl aminocarbonyl, hydroxy C₁-C₃ alkylaminocarbonyl, di(C₁-C₃ alkyl) aminocarbonyl, C₃-C₈ cycloalkylaminocarbonyl, C₁-C₃ alkylthio C₁-C₃ alkyl, C₆-C₁₀ arylthio C₁-C₃ alkyl,halo C₁-C₃ alkyl, hydrazinyl, amino C₁-C₃ alkyl, hydroxy C₁-C₃ alkyl,C₃-C₆ cycloalkylamino, hydroxylamino, and C₂-C₃ alkenyl, wherein thearyl portion is optionally substituted with one or more substituentsselected from halo and C₁-C₃ alkoxy; with the proviso that when R¹¹ ischloro and R¹⁴ is hydrogen, R¹⁰ is not dicyclopentylmethyl; and informula (III), R²⁰ is amino, C₁-C₃ alkoxy, C₁-C₃ alkylamino, hydroxyC₁-C₃ alkylamino, di(C₁-C₃ alkyl)amino, or C₃-C₈ cycloalkylamino, andR²¹ and R²² are independently selected from hydrogen, hydroxyl, amino,mercapto, ureido, C₁-C₆ alkyl carbonylamino, hydroxy C₁-C₆ alkyl, andhydrazinyl; or a pharmaceutically acceptable salt thereof.
 35. Thecompound or salt of claim 34, wherein the compound is a compound offormula (I).
 36. The compound or salt of claim 35, wherein R⁶ ishydrogen.
 37. The compound or salt of claim 35, wherein Y is N.
 38. Thecompound or salt of claim 35, wherein R³ and R⁴ are both hydroxyl. 39.The compound or salt of claim 35, wherein R⁵ is selected from hydroxyland halo.
 40. The compound or salt of claim 35, wherein R² is H orchloro.
 41. The compound or salt of claim 35, wherein the compound is:


42. The compound or salt of claim 34, wherein the compound is of formula(II).
 43. The compound or salt of claim 42, wherein R¹⁵ is hydrogen. 44.The compound or salt of claim 42, wherein Y is N.
 45. The compound orsalt of claim 42, wherein R¹² and R¹³ are both hydroxyl.
 46. Thecompound or salt of claim 42, wherein R¹⁴ is H or chloro.
 47. Thecompound or salt of claim 42, wherein R¹⁴ is H.
 48. The compound or saltof claim 47, wherein the compound is:


49. The compound or salt of claim 42, wherein R¹⁴ is halo C₁-C₃ alkyl orhydroxy C₁-C₃ alkyl.
 50. The compound or salt of claim 49, wherein thecompound is selected from:


51. The compound or salt of claim 34, wherein the compound is a compoundof formula (III).
 52. The compound or salt of claim 51, wherein R²¹ andR²² are both hydroxyl.
 53. The compound or salt of claim 52, wherein thecompound is:


54. A pharmaceutical composition comprising a compound or salt of claim34 and a pharmaceutically acceptable carrier.
 55. A method of inducingand/or maintaining a hypothermic and/or hypometabolic state in a mammalin need thereof comprising administering an effective amount of acompound or salt of claim
 34. 56. The method of claim 55, wherein themammal has been afflicted with at least one of an anoxic, hypoxic, orhypoperfusion event.
 57. The method of claim 56, wherein the anoxic,hypoxic, or hypoperfusion event is selected from birth injury, cardiacarrhythmia, heart attack, cardiac arrest, stroke, brain injury, trauma,and head injury.
 58. The method of claim 55, wherein the mammal issubjected to a surgical procedure.
 59. The method of claim 58, whereinthe compound or salt thereof is administered before, during, or afterthe surgical procedure.
 60. A method of treating a disease or disorderin a mammal in need thereof comprising administering an effective amountof a compound or salt of claim 34, wherein the disease or disorder isselected from chronic pain, acute pain, diabetes, cardiac arrhythmia,myocardial infarction, depression, and brain ischemia.
 61. The method ofclaim 55, wherein the compound or salt is administered as anintrathecal, oral, or parenteral composition.
 62. The method of claim60, wherein the compound or salt is administered as an intrathecal,oral, or parenteral composition.